The study of modulation of brain-immune function and searching for new functional molecule regulated by leptin receptor

众所周知，瘦素是调节食物摄入和体重的重要循环信号。这些作用被认为是通过下丘脑中枢通过Ob-Rb受体介导的。我们发现外周应用瘦素增加了大脑许多区域的白介素(IL)-1b转录本。虽然瘦素在缺乏功能性Ob-Rb受体的db/db小鼠下丘脑中不会诱导STAT3激活或细胞因子信号传导3 （SOCS3）表达抑制，但瘦素增加IL-1b水平的程度与正常小鼠相似。因此，瘦素的一种新功能被认为是通过不依赖stat3的机制在大脑的许多区域诱导IL-1b的表达。尽管瘦素受体存在于大脑的许多区域，但除了下丘脑之外，瘦素靶点的体内功能研究很少。我们证明外周应用瘦素不仅增加了下丘脑的STAT3磷酸化，而且增加了脑干的STAT3磷酸化。免疫组织化学。这些发现反映了脑干和下丘脑中瘦素b- rb受体的生理功能。糖皮质激素可能在反馈抑制免疫/炎症反应中发挥生理作用，地塞米松剂量依赖性地抑制瘦素诱导的下丘脑IL-1b表达。此外，地塞米松抑制瘦素诱导的IL-1b在原代培养的胶质细胞中的表达。相反，地塞米松预处理不能抑制瘦素诱导的下丘脑STAT3磷酸化。因此，我们认为糖皮质激素负向调节瘦素诱导的脑内IL-1b表达。我们研究了双链rna激活蛋白激酶（PKR）作为瘦素可能的信号通路的作用。PKR抑制剂2-氨基嘌呤抑制瘦素诱导的细胞内信号传导。然而，我们观察到瘦素不激活PK，并发现2-氨基嘌呤抑制瘦素信号传导的作用位点是Janus激酶。少

Leptin is known to be an important circulating signal for regulation of food intake and body weight. These effects were suggested to be mediated through the hypothalamic center via the Ob-Rb receptor. We found that peripherally applied leptin increased Interleukin (IL)-1b transcripts in many regions of the brain. Although leptin did not induce STAT3 activation or suppressor of cytokine signaling3 (SOCS3) expression in the hypothalamus of the db/db mice, which lack a functional Ob-Rb receptor, leptin increased the IL-1b levels to similar extents as normal mice. Therefore, a novel function of leptin is suggested as the induction of IL-1b expression in many regions of the brain via STAT3-independent mechanisms.Although leptin receptors exist in many regions of the brain, there have been few in vivo functional studies of leptin's target site other than the hypothalamus. We demonstrated that peripherally applied leptin increased STAT3 phosphorylation not only in the hypothalamus but also in … More the brainstem as assessed by Western blotting and. Immunohistochemistry. These findings represent physiologically functional leptin Ob-Rb receptor in the brainstem as well as in the hypothalamus.Glucocorticoids were suggested to play a physiological role in the feedback inhibition of immune/inflammatory responses Pretreatment with dexamethasone dose dependently inhibited leptin-induced IL-1b expression in the hypothalamus. Moreover, dexamethasone inhibited leptin-induced IL-1b expression in the primary cultured glial cells. In contrast, pretreatment with dexamethasone did not inhibit leptin-induced STAT3 phosphorylation in the hypothalamus. Therefore, it is suggested that glucocorticoid negatively regulates leptin-induced IL-1b expression in the brain.We investigated role of double-stranded RNA-activated protein kinase (PKR) as a possible signaling pathway of leptin. 2-aminopurine, an inhibitor of PKR inhibited leptin-induced intracellular signaling. However, we observed that leptin did not activate PK, and found the site of action of 2-aminopurine to inhibit leptin signaling was Janus kinase. Less